Compositions comprising a toxin conjugated to an antibody selectively reactive to a muscle specific antigen. Methods of using the immunotoxin conjugates for treatment of focal muscle spasms are also provided.
A variety of neurological disorders are characterized by disabling, involuntary muscular spasms. The most successful treatment for focal muscle spasm is intramuscular injection of the botulinum toxin A (BTX), the only pharmaceutical formulation of botulinum toxin currently on the market. Intramuscular injection of BTX weakens the muscles and reduces the symptoms. (Jankovic and Brin, N. Engl. J. Med., (1991) 324:1186-1194; Stell and Moore, History and current applications of botulinum toxin treatment. In: Moore P, ed. Handbook of botulinum toxin treatment. Oxford: Blackwell Science, Inc., 1995:3-15; Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: the clinical usefulness of botulinum toxin-a in treating neurologic disorders. Neurology (1990) 40:1332-1336; Coffield et a. The site and mechanism of action of botulinum neurotoxin. In: Jankovic J, Hallett M, eds. Therapy with botulinum toxin. New York: Marcel Dekker, Inc., (1994) 3-14). However, the therapeutic effect of BTX is transient and as the BTX paralytic effects wane, patients usually receive additional injections. For many patients, repeated exposure to BTX has been accompanied with decreasing efficacy and duration of benefit. Collateral sprouts of denervated motor nerve terminals and increasing titers of toxin neutralizing antibodies are two mechanisms of resistance to BTX (Coffield et al., supra, Jankovic and Schwartz, Neurology (1995) 45:1743-1746). As a result, larger and more frequent doses of BTX become necessary for relief of the spasm, increasing the risk of side-effects. Eventually, some patients become completely refractory to treatment.
Accordingly, what is needed in the art is a means to treat focal muscle disorders with greater specificity and duration of effect. The present invention provides these and other advantages.
In one aspect the present invention is directed to a method of treating a focal muscle spasm. The method comprises the steps of administering, by intramuscular injection, a therapeutically effective dose of an immunotoxin conjugate to a muscle of the focal muscle spasm. The immunotoxin conjugate comprises an antibody conjugated to a toxin selected from the group consisting of: ricin and abrin, and the antibody is selectively reactive, under immunologically reactive conditions, to a nicotinic acetylcholine receptor (nAchR). In preferred embodiments the antibody is a monoclonal antibody. Typically, the mammalian acetylcholine receptor is a human acetylcholine receptor. In particularly preferred embodiments the toxin is ricin. Typically the focal muscle spasm is selected from the group consisting of: blepharospasm, cervical dystonia, hand dystonia, limb dystonia, hemifacial spasm, bruxism, strabismus, VI nerve palsy, spasmodic dysphonia, and oromandibular dystonia. In other embodiments a therapeutically effective amount of the immunotoxin conjugate is administered with a therapeutically effective amount of botulinum toxin, as an immunoconjugate or in unconjugated form.
In another aspect the present invention relates to a method of treating a focal muscle spasm. The method comprises the steps of administering, by intramuscular injection, a therapeutically effective dose of an immunotoxin conjugate to a muscle of the focal muscle spasm. The immunotoxin conjugate comprises an antibody conjugated to a galactose binding moiety and a toxin selected from the group consisting of: ricin-A and abrin-A, and the antibody is selectively reactive, under immunologically reactive conditions, to a nicotinic acetylcholine receptor (nAchR). In some embodiments the galactose binding moiety is selected from the group consisting of: ricin-B and abrin-B. In preferred embodiments the antibody is a monoclonal antibody. Typically, the mammalian acetylcholine receptor is a human acetylcholine receptor. In particularly preferred embodiments the toxin is ricin. Typically the focal muscle spasm is selected from the group consisting of: blepharospasm, cervical dystonia, hand dystonia, limb dystonia, hemifacial spasm, bruxism, strabismus, VI nerve palsy, spasmodic dysphonia, and oromandibular dystonia.
In another aspect the present invention relates to an immunotoxin conjugate, comprising an antibody conjugated to a toxin selected from the group consisting of: ricin and abrin, where the antibody is selectively reactive, under immunologically reactive conditions, to a mammalian nicotinic acetylcholine receptor. In preferred embodiments the antibody is a monoclonal antibody. Typically, the mammalian acetylcholine receptor is a human acetylcholine receptor. In particularly preferred embodiments the toxin is ricin.